Doctoral Thesis
Refine
Year of publication
Document Type
- Doctoral Thesis (5741) (remove)
Language
- German (3643)
- English (2069)
- French (9)
- Latin (5)
- Spanish (5)
- Portuguese (4)
- Italian (3)
- Multiple languages (2)
- mis (1)
Is part of the Bibliography
- no (5741)
Keywords
- Deutschland (15)
- Gentherapie (14)
- HIV (13)
- Apoptosis (12)
- Membranproteine (12)
- NMR-Spektroskopie (11)
- RNA (11)
- RNS (10)
- Schmerz (10)
- ALICE (9)
Institute
- Medizin (1531)
- Biowissenschaften (836)
- Biochemie und Chemie (729)
- Physik (597)
- Pharmazie (329)
- Biochemie, Chemie und Pharmazie (311)
- Geowissenschaften (139)
- Neuere Philologien (115)
- Gesellschaftswissenschaften (111)
- Psychologie (97)
Lipid mediators have been referred as bioactive lipids, whose change in lipid levels resulted in functional or pathophysiological consequences. They are in the focus of biological research, nevertheless this is a late recognition due to the many difficulties of working with bioactive lipids due to their properties: hydrophobic, unstable and they occur in only in small quantities. Liquid chromatography and mass spectrometry have facilitated the work with them. Especially in this field, cardiovascular diseases and inflammatory mediated diseases and cancer are pathophysiological events where LMs are deregulated. Additionally, if the modulation of one LM pathway is not sufficient to overcome a disease, the combination of targeting two or more pathways could be effective. Needless to say, lipid signaling cascades are complicated pathways and possible shunting into other pathways when inhibiting or genetically deleting enzymes should be taken into consideration.
The first part of this work has focused on enzymes that metabolize eicosanoids, like mPGES-1 and 5-LO. mPGES-1 is an important enzyme metabolizing PGH2 and one of the key players of the AA cascade. Its product, PGE2 plays an important role in different inflammatory processes. Inhibition of the mPGES-1 might be a promising step to circumvent COX dependent side effects of NSAIDs. The class of quinazoline compounds around the lead structure FR20 has been investigated on isolated human and murine enzyme, in HeLa cells and in different human whole blood (HWB) settings to establish the possible effects of these compounds on eicosanoid profiling. Novel compounds with inhibitory activities in the submicromolar range (IC50: 0.13 µM - 0.37 µM on isolated enzyme) were obtained which were also effective in cells and HWB. Furthermore, pharmacological profiling of toxicity and lipid screening with LC/MS-MS revealed that compounds also reduce PGE2 levels in intact cells and whole blood; they do not impair cell viability but lack the ability to inhibit the murine mPGES-1 enzyme. This problem could be overcome by means of chemical synthesis varying the scaffold (quinoline, quinazoline) or introducing biosteric replacement in the phenyl moieties.
5-LO is a relevant enzyme that plays an important role in eicosanoid signaling in particular in leukotriene biosynthesis. Leukotrienes are involved in asthma, allergic rhinitis, glomerulonephritis, rheumatoid arthritis, sepsis, cancer and atherosclerosis. Moreover, genetic variants in the genes of the 5-LO pathway have been associated with the risk of development of acute myocardial infarction and stroke. Eicosanoids are increased in infectious exacerbations of chronic obstructive pulmonary disease (COPD). They are also elevated in the airways of stable COPD patients compared to healthy subjects. Therefore, 5-LO has attired the scientific community as a possible therapeutic target to treat the several disease conditions listed before. In this study an extensive evaluation of imidazo[1,2-a]pyridines as a suitable lead structure for novel 5-LO targeting compounds was presented Within the three publications, 5-LO inhibitory activity of synthesized compounds was investigated in intact PMNL, a cell-free assay, in human whole blood and rodent cells to both elucidate structure-activity relationships and compounds were in vitro pharmacological evaluated. Chemical modifications for lead optimization via straight forward synthesis were used to combine small polar groups (hydroxy, and methoxy groups) which led to a suitable candidate with desired in vitro pharmacokinetic profile in terms of solubility and intrinsic clearance without showing any cytotoxicity. More than 70 imidazo[1,2-a]pyridine derivatives have been synthesized, resulting in more than 50 active compounds. Although it was not possible to introduce a solubility group without impairing the 5-LO inhibitory activity, combination of small polar groups lead to a more favorable solubility and in vitro metabolic stability. Overall, the development of 5-LO inhibitors with high efficacy and selectivity in vivo will provide a possible treatment for patients having one of the diseases where leukotriene biosynthesis plays an important role.
Other types of 5-LO inhibitors have been synthesized during this work, NO-NSAIDs can be postulated as novel 5-LO inhibitors that could circumvent the undesired side-effects of inhibiting COX isoforms (ulcer perforation, gastrointestinal bleeding and in some cases death). It is suggested that NO group is released in situ or after compounds are metabolized. NO-NSAIDs maintain the same anti-inflammatory properties by inhibiting 5-LO in clinical relevant concentrations. NO-NSAIDs are currently under clinical trial for the treatment of diseases where inflammation plays an important role. Synthesis of NO-NSAIDs is straightforward and can be applied for most NSAIDs recently published. Among them, the most promising candidate is NO-sulindac that was able to inhibit 5-LO product formation in intact PMNL, purified 5-LO and HWB in micromolar concentration. Additional experiments regarding their mechanism are currently being performed.
The present study could show that dual inhibitors are an interesting approach that is practicable. It has been used in the recent years to overcome side-effects and diseases concerning more pathophysiological conditions. MetS is an example of a conjunction of symptoms: hyperglycemia, hypertriglyceridemia, hypertension and obesity. Due to its complex nature, the current treatment strategies of MetS require multiple pharmacological compounds regulating lipid and glucose homeostasis as well as blood pressure and coagulation. This study describes the first synthesis of dual sEH/PPAR modulators as potential agents for treatment of MetS. Following a combinatorial approach, an acidic head group known as a pharmacophore important for PPARα/γ dual agonistic activity was combined with different hydrophobic urea derivatives in order to introduce an epoxide mimetic (sEH pharmacophore). The resulting compounds yielded high inhibition of sEH and different patterns of PPAR agonistic activity. This study demonstrates that the pharmacophores of PPAR agonists and sEH inhibitors can be easily combined, resulting in a simplified blueprint of a dual sEH/PPAR modulator. Further in vivo pharmacological evaluation studies are needed in order to evaluate, which pattern of PPAR activation shows the most promising profile for treatment of metabolic syndrome.
Another example of dual pharmacology has been presented in this work. Natural products derived compounds were able to target sEH and exhibit promising antiproliferative properties. The principle of addressing multiple targets by natural products can be transferred to synthetic multi-target ligands. In conclusion, several (E)-styryl-1H-benzo[d]imidazoles were synthesized and evaluated on recombinant sEH after an initial hit (IPS) that lead to potent sEH inhibitors exhibiting antiproliferative activities. Following the natural product-inspired design, the desired biological activity from a bacterial secondary metabolite has been enhanced and transferred to a synthetic compound series. The resulting compounds were accessible via an easy synthetic route and offered a possibility to investigate the structure-activity relationships. The natural product inspired drug design extends the valuable role of natural products as drugs and drug precursors to templates for fully synthetic bioactive molecules. Simplification of natural products by means of chemical synthesis could lead to an interesting field in the treatment of cancer.
Affinity chromatography has been used to unravel unknown- and off-target effects which either contribute to the biological effect of the inhibitor or that counteract or lead to undesired side-effects. During this PhD work, two main projects related to this technique have been established. In the first one, related to an imidazo[1,2-a]pyridine inhibitor (EP6), it has been shown that epoxide-sepharose is a reliable material in order to couple compounds bearing an alcohol. Coupling of an analogue of EP6 to the sepharose has been accomplished and affinity towards 5-LO was demonstrated. The challenging step is to discern from unspecific protein binders and analysis via SDS-PAGE separation and mass spectrometry. Further experiments using other cell types or improving SDS-PAGE analysis (e.g. 2D gel analysis) should be useful to unravel EP6 off-target effect. During the second project related to off-target effects of celecoxib and DMC, the main problem was the coupling of the functional group to the sepharose. Affinity towards COX-2 could not be demonstrated pointing out the inefficient coupling method. Higher pH values during coupling reaction should be tested in further experiments. Nevertheless, affinity chromatography is a useful technique to unravel cellular mechanisms.
Sphingolipid metabolism is also a recent area that attired the attention of cancer researchers, due to their important roles in cell proliferation and apoptosis. Ceramide metabolism inhibitors were synthesized and evaluated on different assay systems in order to assess their efficacy on several cancer lines. Remarkably, 2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (32) was a useful scaffold to mimic the sphingoid base. This key intermediate was used to produce ceramide analogues that could enter the cell and target apoptosis machinery. EB143 (38) increased ceramide levels in an in vitro ceramide synthase assay in a dose-response manner meaning that ceramide synthase was not inhibited but the ceramide de novo synthesis was activated. This effect was due to the fact that EB143 is a cytotoxic compound with an interesting antiproliferative profile. Further chemical modifications should be carried out to modulate this effect.
COX and LO inhibitors are cancer-preventive not only by inhibiting specific antiapoptotic AA metabolites but also by facilitating accumulation of AA which promotes neutral SMase activity and increases the proapoptotic ceramide. Several 5-LO inhibitors have been evaluated on several cancer lines and sphingolipid levels were measured in order to obtain a relationship. A549, Capan-2 and MCF-7 cells line were incubated with synthetic 5-LO inhibitors and zileuton. Compounds were cytotoxic to all cancer cell lines except from A549. Needless to say, zileuton did not exhibit a cytotoxic profile. Synthetic 5-LO inhibitors were able to modify ceramide levels but were useless when coincubating with sphingolipid metabolism inhibitors (myoricin, amitryptiline etc.) and inconsistent results were obtained. On the contrary, zileuton selectively increased Cer-C16 levels and in less extend Cer-C24:1. When using a SPT inhibitor (myoricin) alone was able to reduce C24:1 and Cer-C16:0 levels below the control, a similar effect occurred when incubation the cells with zileuton and myriocin. Interestingly, treatment of zileuton together with either amitryptiline or desipramine led to a decrease in Cer-C24:1 and levels Cer-C16:0 but the inhibition was not complete indicating that probably the de novo pathway has an important role. Further investigations on mRNA level should be carried out in order to discern which CerS is activated.
The main objective of the present thesis was the synthesis of lipid signaling modulators and their evaluation in vitro as therapeutic strategy to overcome pathophysiological conditions (cancer, metabolic syndrome, etc). It has been accomplished on many relevant targets like 5-LO, mPGES-1, sEH and PPAR and these lipid signaling modulators could be used in the treatment of diseases conditions where lipid mediators play an important role.
Die im Mittelhirn lokalisierten dopaminergen (DA) Neurone sind in einer Vielzahl von Hirnfunktionen involviert und werden aufgrund von anatomischen, molekularen sowie funktionellen Unterschieden in mehrere Subpopulationen aufgeteilt. DA Neurone, die in der Substantia nigra (SN) pars compacta lokalisiert sind, spielen durch ihre Projektion in das dorsale Striatum eine Rolle in der Steuerung der Willkürmotorik. Die Area tegmentalis ventralis (VTA) enthält DA Neurone, die in den präfrontalen Cortex, die basolateralen Amygdala sowie den Nucleus accumbens projizieren und in höheren kognitiven Funktionen, wie dem Arbeitsgedächtnis, der Motivation sowie belohnungsassoziierten Lernvorgängen involviert sind.
In dieser Arbeit wurden die differentiellen Eigenschaften des transienten A-Typ Kaliumstroms sowie dessen Funktion für die intrinsische elektrische Aktivität und die Integration von synaptischen Eingängen in Subpopulationen von DA Neuronen untersucht. Dieser spannungsgesteuerte Strom ist an der Kontrolle der Schrittmacheraktivität beteiligt, beeinflusst die Form und Dauer von Aktionspotentialen und moduliert die Erregbarkeit des somatodendritischen Kompartiments. Der A-Typ Kaliumkanal besteht in DA Neuronen aus einem Tetramer von porenbildenden KV4.3 α-Untereinheiten. Die Koexpression von akzessorischen β-Untereinheiten moduliert maßgeblich die biophysikalischen Parameter des A-Stroms, wie z. B. die Kinetik der Inaktivierung sowie die Spannungsabhängigkeit der Aktivierung und Inaktivierung. Zu diesen β-Untereinheiten gehören die cytoplasmatischen Kaliumkanal-interagierenden Proteine (KChIPs) sowie die transmembranären Dipeptidylpeptidase-ähnlichen Proteine (DPPLs). Während in DA SN Neuronen vor allem KChIP3 exprimiert wird und einen schnell inaktivierenden A-Strom gewährleistet, sind DA VTA Neurone durch die zusätzliche Expression der KChIP4a Splice-Variante charakterisiert, welche durch Inhibition der schnellen Inaktivierung in einem langsam inaktivierenden A-Strom resultiert. Die Bedeutung der differentiellen KChIP4a-Expression für DA Mittelhirnneurone wurde mit Hilfe von KChIP4-Knock-Out (KO)-Mäusen untersucht. Alle Versuche wurden in vitro an akuten Hirnschnitten adulter Wildtyp (WT)- und KChIP4-KO-Tiere durchgeführt und die DA neurochemische Identität sowie die Lage der gemessenen Zellen im Anschluss immunhistochemisch bestätigt. Die biophysikalischen Eigenschaften des A-Stroms wurden mit der Patch-Clamp Technik in der nucleated outside-out Konfiguration untersucht, welche optimale Bedingungen für Voltage-Clamp Experimente gewährleistet. Der A-Strom in DA VTA Neuronen aus KChIP4-KO-Tieren wies dabei eine siebenfach schnellere Inaktivierungskinetik als in vergleichbaren Neuronen aus WT-Tieren auf, während die Inaktivierungskinetik in DA SN Neuronen aus KChIP4-KO-Tieren lediglich um den Faktor zwei schneller war. Außerdem wurde festgestellt, dass selektiv in DA VTA Neuronen das halbmaximale Aktivierungspotential ebenfalls von der KChIP4-Expression abhängig war. Somit konnte gezeigt werden, dass die Expression von KChIP4 für die charakteristischen A-Strom-Eigenschaften von DA VTA Neuronen verantwortlich ist.
Die funktionelle Rolle des KChIP4-vermittelten langsamen A-Stroms wurde mit Hilfe von Current-Clamp Messungen in Ganzzellableitungen untersucht. Dabei wurde deutlich, dass die Expression von KChIP4 die Spontanaktivität von DA SN und VTA Neuronen nicht beeinflusst. Das für DA VTA Neuronen charakteristische verzögerte Wiedereintreten der Spontanaktivität nach einer Inhibition zeigte allerdings eine Abhängigkeit von der KChIP4-Expression, da der sog. rebound delay in DA VTA Neuronen aus KChIP4-KO-Tieren signifikant kürzer war, als in Zellen aus WT-Tieren. Dies konnte sowohl durch Strominjektionen, die in ihrer Kinetik GABAergen synaptischen Eingängen ähnelten, als auch nach direkter Aktivierung von GABA-Rezeptoren durch iontophoretische GABA-Applikation bestätigt werden. KChIP4 könnte somit einen internen Verzögerungsmechanismus nach einer transienten Inhibition von DA Neuronen gewährleisten, die z.B. bei Präsentation von aversiven Stimuli sowie beim Ausbleiben von erwarteten Belohnungen auftritt. Somit könnte die physiologische Relevanz des KChIP4-gesteuerten A-Stroms in der Integration von inhibitorischen synaptischen Eingängen im Kontext von belohnungsgesteuerten Lernprozessen liegen.
The human brain is an unparalleled system: Through millions of years of evolution and during a lifespan of learning, our brains have developed remarkable abilities for dealing with incoming sensory data, extracting structure and useful information, and finally drawing the conclusions that result in the actions we take. Understanding the principles behind this machinery and building artificial systems that mimic at least some of these capabilities is a long standing goal in both the scientific and the engineering communities. While this goal still seems unreachable, we have seen tremendous progress when it comes to training data-driven algorithms on vast amounts of training data, e.g. to learn an optimal data model and its parameters in order to accomplish some task. Such algorithms are now omnipresent: they are part of recommender systems, they perform speech recognition and generally build the foundation for many semi-autonomous systems. They start to be integral part of many technical systems modern technical societies rely on for their everyday functioning. Many of these algorithms were originally inspired by biological systems or act as models for sensory data processing in mammalian brains. The response properties of a certain population of neurons in the first stages of the mammalian visual pathway, for example, can be modeled by algorithms such as Sparse Coding (SC), Independent Component Analysis (ICA) or Factor Analysis (FA). These well established learning algorithms typically assume linear interactions between the variables of the model. Most often these relationships are expressed in the form of a matrix-vector products between a matrix with learned dictionary-elements (basis vectors as column vectors) and the latent variables of these models. While on the one hand this linear interaction can sometimes be justified by the physical process for which the machine learning model is proposed, it is on the other hand often chosen just because of its mathematical and practical convenience. From an optimal coding point of view though, one would generally expect that the ideal model closely reflect the core interactions of the system it is modeling. In vision for example, one of the dominant processes giving rise to our sensory percepts are occlusions. Occluding objects are omnipresent in visual scenes and it would not be surprising if the mammalian visual system would be optimized to process occluding structures in the visual data stream. Yet, the established mathematical models of the first stages of the visual processing path (like, e.g., SC, ICA or FA) all assume linear interactions between the active image components. In this thesis we will discuss new models that aim to approximate the effects of occluding components by assuming nonlinear interactions between their activated dictionary elements. We will present learning algorithms that infer optimal parameters for these models given data. In the experiments, we will validate the algorithms on artificial ground truth data and demonstrate their ability to recover the correct model parameters. We will show that the predictions made by these nonlinear models correspond better to the experimental data measured in-vivo than the predictions made by the established linear models. Furthermore, we systematically explore and compare a large space of plausible combinations of hyperparameters and preprocessing schemes in order to eliminate any effects of artefacts on the observed results. Training nonlinear sparse coding models is computationally more demanding than training linear models. In order to perform the numerical experiments described in this thesis we developed a software framework that facilitates the implementation of massive parallel expectation maximization (EM) based learning algorithms. This infrastructure was used for all experiments described in here, as well as by collaborators in projects we will not discuss. Some of the experiments required more than 1017 floating point operations and were run on a computer cluster running on up to 5000 CPU Cores in parallel. Our parallel framework enabled these experiments to be performed.
Ziel der vorliegenden prospektiven, experimentellen, randomisierten kontrollierten In-vitroStudie war es, zwei Dentinadhäsive, die der sechsten (One-Up-Bond F, Tokuyama) und siebten (G-Bond, GC Tokio) Generation angehören, unter ISO-Bedingungen zu untersuchen und einer Kontrollgruppe (Clearfil SE, Kuraray), die der sechsten Generation zugeordnet wird, gegenüberzustellen. Neunzig unversehrte humane Molaren der zweiten Dentition wurden eingebettet. Das Dentin wurde mit Siliziumcarbidscheiben der Körnung 600 bearbeitet, um eine Schmierschicht zu erhalten. Anschließend wurden die Dentinproben randomisiert in drei Gruppen eingeteilt und die jeweiligen Dentinadhäsive wurden nach Herstellerangaben appliziert. Mittels einer Versuchsapparatur, die in Anlehnung an die ISO/TS 11405:2003 hergestellt wurde, wurde das Kompositmaterial Tetric EvoCeram in der Farbe A2 aufgetragen und lichtgehärtet. Eine Alterung der Proben fand bei 500 Thermocycling-Zyklen bei Temperaturen von 5°C und 55°C statt. Mit einer Universalprüfmaschine Zwicki (Vorschubgeschwindigkeit 0,5 mm/min) wurde die Scherhaftfestigkeit der Proben bestimmt. Anschließend wurden die abgescherten Dentinproben unter dem Rasterelektronenmikroskop bei einer Vergrößerung von 20-fach und 2000-fach bezüglich der auftretenden Frakturmodi untersucht.
Die Haftkraft-Mittelwerte von Clearfil SE betrugen 4,22 MPa, von G-Bond 3,83 MPa und von One-Up-Bond F 7,11 MPa. Bei der statistischen Analyse mittels Kruskal-Wallis-Test wurde die Signifikanz ermittelt. Eine Signifikanz zwischen den Dentinadhäsiven One-UpBond F und G-Bond lag vor. Einzig Clearfil SE war statistisch nicht signifikant gegenüber den anderen Produkten. Die Bruchanalyse ergab, dass G-Bond eine hohe Anzahl (46,7 %) an kohäsiven Frakturen aufwies, Clearfil SE mehr als die Hälfte (66,7 %) gemischte Frakturen und dass One-Up-Bond F kaum adhäsive (3,3 %) Frakturen zeigte, sondern hauptsächlich (80 %) gemischte Brüche. Signifikante Unterschiede waren zwischen dem Bruchverhalten von Clearfil SE und G-Bond sowie zwischen G-Bond und One-Up-Bond F zu beobachten.
Unter der Limitation der vorliegenden In-vitro-Studie erscheint die Anwendung von G-Bond aufgrund der erhaltenen statistisch signifikant niedrigeren Haftwerten als nicht empfehlenswert.
Silicon wafers such as Silicon on Insulator (SOI) and strained silicon on Insulator (sSOI) are the essential and basic materials of advanced microelectronic devices. However, they often show various kinds of crystal defects which impair the function of these devices. The most efficient method to date, for detecting such defects and for determining their density, is to delineate them by etching the wafers with a suitable etching solution and characterise them via light optical microscopy. Etch pits are formed at defect sites which are etched at a faster rate than at the perfect lattice. The standard etching solution used for SOI and sSOI is a dilute version of Secco. As Secco contains carcinogenic and environmentally hazardous chromium (VI), the use of which is or will be restricted by law in many countries, suitable chromium (VI)-free etching solutions like Organic Peracid Etches (OPE), modified Chemical Polishing Etches (CP) like CP4 mod and mixtures with organic oxidizing agents like chloranil (CA) have been developed for the successful delineation of various types of crystal defects.
However there are still nanometer-sized defects which are hard to detect or escape detection by this method. Copper decoration is a well known method to magnify these defects. It consists in applying a copper nitrate solution to the back of the SOI or sSOI wafer. On annealing, copper diffuses through the substrate and the BOX (buried oxide) to the SOI/sSOI film and on quenching to room temperature, copper precipitates as copper silicide, SiCu3, foremost at crystal defects where the lattice strain is greater than at perfect lattice sites. These silicides increase the volume in these parts of the crystal lattice and defect magnification occurs. A considerable disadvantage of this method is its tendency for artefact formation, when the copper concentration used is too high, with the copper precipitating at the film surface. The consequence is a higher density of etch pits whereby true defect etch pits cannot be differentiated from those caused by artefacts.
The aim of this thesis is to show that the processes of decorating and etching can be combined successfully to delineate all crystal defects in SOI and sSOI. An ideal result would have been to find a copper decoration procedure that decorates all existing crystal defects at a copper concentration that avoids artefact formation.
Protein quality control systems (PQC), i.e. UPS and aggresome-autophagy pathway, have been suggested to be a promising target in cancer therapy. Simultaneous pharmacological inhibition of both pathways have shown increase efficacy in various tumors, such as ovarian and colon carcinoma. Here, we investigate the effect of concomitant inhibition of 26S proteasome by FDA-approved inhibitor Bortezomib, and HDAC6, as key mediator of the aggresome-autophagy system, by the highly specific inhibitor ST80 in rhabdomyosarcoma (RMS) cell lines. We demonstrated that simultaneous inhibition of 26S proteasome and selective aggresome-autophagy pathway significantly increases apoptosis in all tested RMS cell lines. Interestingly, we observed that a subpopulation of RMS cells was able to survive the co-treatment and, upon drug removal, to recover similarly to untreated cells. In this study, we identified co-chaperone BAG3 as the key mediator of this recovery: BAG3 is transcriptionally up-regulated specifically in the ST80/Bortezomib surviving cells and mediates clearance of cytotoxic protein aggregates by selective autophagy. Impairment of the autophagic pathway during the recovery phase, both by conditional knock-down of ATG7 or by inhibition of lysosomal degradation by BafylomicinA1, triggers accumulation of insoluble protein aggregates, loss of cell recovery and cell death similarly to stable short harpin RNA (shRNA) BAG3 knock-down. Our results are the first demonstration that BAG3 mediated selective autophagy is engaged to cope with proteotoxicity induced by simultaneous inhibition of constitutive PQC systems in cancer cell lines during cell recovery. Moreover, our data give new insights in the regulation of constitutive and on demand PQC mechanisms pointing to BAG3 as a promising target in RMS therapy.
Am Ende seiner Tage sprach der König Salomon: "Die Sonne geht auf und unter [...]. Was gewesen ist, wird [wieder] sein, was getan worden ist, wird [wieder] getan, und es gibt nichts Neues unter der Sonne".1 Im August des Jahres 1881, beim Spaziergang durch die Wälder am See von Silvaplana, bei einem mächtigen, pyramidal aufgetürmten Block, "6000 Tausend Fuß jenseits von Mensch und Zeit" kam einem Professor der klassischen Philologie jener Gedanke wieder – der Gedanke der "Ewigen Wiederkunft des Gleichen", die er später als das Hauptprinzip der altgriechischen Zeitauffassung formulierte. Der Professor hieß Friedrich Nietzsche.2 Mehr als hundert dreißig Jahre sind nach seinem Spaziergang vergangen, und mehr als hundert dreißig Jahre dauert die Diskussion über die zyklische und lineare Zeit. Es wurde mehrmals behauptet und wieder verworfen, dass der Hauptunterschied zwischen dem "hebräischen" und "griechischen" Denken, zwischen den "Gläubigen" und den "Heiden" gerade in dieser Zeitauffassung besteht. Die mythische Zeit der Griechen sei räumlich und statisch, sie habe kein Ziel und keinen Zweck, sie wandle im ewigen Kreislauf gefühllos und träge, ohne Anfang und Ende, ohne Wohin und Woher, ohne Hoffnung. Die Zeit der Tora hingegen sei zielgerichtet. Die Erschaffung der Welt und die Sintflut, der Auszug aus Ägypten und die Wüstenwanderung – all dies seien einmalige Ereignisse, welche sich nie wiederholen würden. Sie alle hätten einen Zweck – die Erlösung der Menschheit. Jede von ihnen sei ein Fortschritt – ein Schritt auf dem Pfad der Geschichte, der Geschichte mit Anfang und Ende, mit Wohin und Woher, mit Hoffnung.3
Die vorliegende Arbeit beabsichtigt nicht, die intuitive Völkerpsychologie zu untersuchen. Vielmehr handelt es sich hier um die Vorstellungen einer begrenzten Gruppe der mittelalterlichen jüdischen Intellektuellen aus dem Spanien des 12. Jhs. Ihre Gedanken waren gleichzeitig von der griechischen Philosophie und dem jüdischen Messianismus geprägt. Eben diese eigenartige Kombination macht die Frage nach ihrer Zeitauffassung so spannend. Als Quelle bei einer solchen Fragestellung scheinen mir die beiden Bücher des Rabbi Abraham Ibn Daud von Interesse zu sein – sein Geschichtsbuch Sefer ha-Qabalah (SQ) und sein philosophisch-theologisches Traktat Al-ʿAqīdah ar-Rafīʿah (AR).
Abraham Ibn Daud, Geschichtsschreiber, Philosoph, Astronom, vermutlich auch Arzt, wurde geboren um 1110 in Cordoba, der Hauptstadt des umayyadischen Kalifates und dem kulturellen Zentrum Andalusiens des 12. Jhs. Er war ein Sohn der Tochter des berühmten Gelehrten Isaak Albaliyah.4 Die Erziehung genoss er im Hause dessen Sohnes, seines Onkels, und dem Schüler von Isaak Alfasi, – Baruch Albaliyah.5 Aus seinen Schriften kann man schließen, dass er ausreichende Kenntnisse sowohl in der Bibel, dem Talmud, der hebräischen Poesie als auch in den Naturwissenschaften und der griechischen Philosophie besaß. Darüber hinaus soll er auch mit der polemischen Literatur der Christen, der Moslems und der Karäer, eventuell auch mit dem Evangelium und dem Koran vertraut gewesen sein. Von seinen Werken sind uns sieben bekannt, zwei davon allerdings nur ihrem Namen nach.6 Das auf Arabisch verfasste theologisch-philosophische Traktat Al-ʿAqīdah ar-Rafīʿah (AR, "Der erhabene Glaube") ist nur in zwei hebräischen Übersetzungen aus dem 14. Jh. – Emunah Ramah (ER)7 von R. Salomon Ben Labi und Emunah Niśʾah (EN)8 von R. Samuel Moṭoṭ erhalten.9 Das traditionshistorische Buch Sefer ha-Qabalah (SQ, "Buch der Tradition")10 wurde auf Hebräisch verfasst und von drei weiteren ebenso auf Hebräisch geschriebenen Werken begleitet: Divrey Malkey Yisraʾel (DMY, "Geschichte der Könige Israels"),11 Midraš Zeḫaryah (MZ, "Auslegung der Prophetie Sacharjas")12 und Zeḫer Divrey Romi (ZDR, "Chronik der römischen Geschichte").13
Aim: The aim of this study was to measure cortico-cortical connectivity in multiple sclerosis (MS) patients by TMS-evoked potential (TEP) latencies in EEG evoked by transcranial magnetic stimulation (TMS) of the hand area of the primary motor cortex of one hemisphere. TEPs were recorded on the stimulated- and at the homologue site in the non-stimulated contralateral hemisphere. Both interhemispheric directions were tested. Interhemispheric latencies of the two main reproducible TEPs, the positive component at 60 ms and the negative component at 100 ms (P60 and N100, respectively), were expected to be significantly prolonged in MS-patients compared to healthy volunteers.
Material and methods: The study compared interhemispheric propagation of P60 and N100 in groups of 12 patients with early-stage relapsing-remitting MS (RRMS) and 16 age- and gender-matched healthy controls. The study was approved by the Ethics Committee of the Medical Faculty of the Goethe-University of Frankfurt/Main and conformed to the latest revision of the Declaration of Helsinki of 2008. TEPs were recorded by means of EEG and their latencies were statistically evaluated in 10 channels around the stimulation site and in 10 corresponding electrodes in the non-stimulated contralateral hemisphere. Interhemispheric conduction time was calculated by the difference of TEP latency in non-stimulated vs. stimulated hemisphere.
Results: An ANOVA on interhemispheric conduction time showed a significant prolongation for the N100 from left to right hemisphere in MS compared to controls, while no group differences were found for the P60 and the N100 from right to left hemisphere.
Conclusion: The results provide first evidence that the N100 may constitute an interesting marker to measure interhemispheric conduction delays in early-stage RRMS. The specificity of the present finding and its relation to fiber tract pathology should be examined in further correlative analyses with diffusion tensor imaging and other structural MRI data.